Current Oncology Reports

, 20:2 | Cite as

Checkpoint Inhibitors, Palliative Care, or Hospice

  • Mellar P. DavisEmail author
  • Rajiv Panikkar
Palliative Medicine (A Jatoi, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Palliative Medicine



Checkpoint (CTLA-4, PD-1, and PD-L1) inhibitors have changed the face of oncology. A subset of patients enjoys long, gratifying treatment responses. Unfortunately, most patients do not respond even when expressing favorably markers such as PD-L1. Checkpoint inhibitors are largely palliative (though a subset have long-term cancer responses) and as such patient-related outcome measures should be included when evaluating benefits. The purpose of this review is to place checkpoint inhibitor trials within a palliation context. Included is a discussion on potential adverse effects on end-of-life care.

Recent Findings

Pivotal studies have presented efficacy and safety data but we have little published data on quality of life or symptom responses. Extension of life is approximately 2–3 months with some long-term responses in a minority of patients. The cost of checkpoint inhibitors is high for utility (as measured by quality-adjusted life-year saved) and ranges from 81,000 to over 200,000 USD for quality-adjusted life-year saved. Adverse effects were suboptimally reported in multiple studies. Meaningful responses in many trials as defined by the European Society of Medical Oncology are modest.


Because at least for now, checkpoint inhibitors are used in advanced cancer and largely palliative patients should be seen by palliative specialists, symptoms related to cancer assessed, and advanced directives addressed. Treatment-related autoimmune diseases represent toxicities which oncologists and palliative specialists must understand. This means that palliative care specialists should know about the benefits and adverse effects of these agents. Whether checkpoint inhibitors increase or decrease aggressive care, hospice referrals, and costs at the end of life is yet to be determined.


Checkpoint Inhibitors Utility Value Immune Response 


Compliance with Ethical Standards

Conflict of Interest

Mellar P. Davis and Rajiv Panikkar declare they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Herbst RS, Baas P, Kim DW, Felip E, Perez-Gracia JL, Han JY, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387(10027):1540–50. Scholar
  2. 2.
    Tomita Y, Fukasawa S, Shinohara N, Kitamura H, Oya M, Eto M, et al. Nivolumab versus everolimus in advanced renal cell carcinoma: Japanese subgroup analysis from the CheckMate 025 study. Jpn J Clin Oncol. 2017:1–8.Google Scholar
  3. 3.
    Motzer RJ, Rini BI, McDermott DF, Redman BG, Kuzel TM, Harrison MR, et al. Nivolumab for metastatic renal cell carcinoma: results of a randomized phase II trial. J Clin Oncol. 2015;33(13):1430–7. Scholar
  4. 4.
    Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. Nivolumab versus Everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1803–13. Scholar
  5. 5.
    Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus Docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373(2):123–35. Scholar
  6. 6.
    Fehrenbacher L, Spira A, Ballinger M, Kowanetz M, Vansteenkiste J, Mazieres J, et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet. 2016;387(10030):1837–46. Scholar
  7. 7.
    Goldberg SB, Gettinger SN, Mahajan A, Chiang AC, Herbst RS, Sznol M, et al. Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. Lancet Oncol. 2016;17(7):976–83. Scholar
  8. 8.
    Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372(26):2521–32. Scholar
  9. 9.
    Harrington KJ, Ferris RL, Blumenschein G, Jr., Colevas AD, Fayette J, Licitra L, et al. Nivolumab versus standard, single-agent therapy of investigator’s choice in recurrent or metastatic squamous cell carcinoma of the head and neck (CheckMate 141): health-related quality-of-life results from a randomised, phase 3 trial. Lancet Oncol 2017, 18, 8, 1104, 1115,
  10. 10.
    Hodi FS, Chesney J, Pavlick AC, Robert C, Grossmann KF, McDermott DF, et al. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol. 2016;17(11):1558–68. Scholar
  11. 11.
    Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372(21):2006–17. Scholar
  12. 12.
    Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372(4):320–30. Scholar
  13. 13.
    Ferris RL, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra L, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med. 2016;375(19):1856–67. Scholar
  14. 14.
    Rizvi NA, Mazieres J, Planchard D, Stinchcombe TE, Dy GK, Antonia SJ, et al. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol. 2015;16(3):257–65. Scholar
  15. 15.
    •• Nishijima TF, Shachar SS, Nyrop KA, Muss HB. Safety and tolerability of pd-1/pd-l1 inhibitors compared with chemotherapy in patients with advanced cancer: a meta-analysis. Oncologist, 22. 2017;(4):470–9. This is a very good review on the comparisons between chemotherapy and checkpoint inhibitors. Google Scholar
  16. 16.
    Friedman CF, Proverbs-Singh TA, Postow MA. Treatment of the immune-related adverse effects of immune checkpoint inhibitors: a review. JAMA Oncol. 2016;2(10):1346–53. Scholar
  17. 17.
    Gettinger SN, Horn L, Gandhi L, Spigel DR, Antonia SJ, Rizvi NA, et al. Overall survival and long-term safety of nivolumab (anti-programmed death 1 antibody, BMS-936558, ONO-4538) in patients with previously treated advanced non-small-cell lung cancer. J Clin Oncol. 2015;33(18):2004–12. Scholar
  18. 18.
    Del Paggio JC, Azariah B, Sullivan R, Hopman WM, James FV, Roshni S, et al. Do contemporary randomized controlled trials meet ESMO thresholds for meaningful clinical benefit? Ann Oncol. 2017;28(1):157–62. Scholar
  19. 19.
    Bentley TGK, Cohen JT, Elkin EB, Huynh J, Mukherjea A, Neville TH, et al. Measuring the value of new drugs: validity and reliability of 4 value assessment frameworks in the oncology setting. J Manag Care Spec Pharm. 2017;23(6-a Suppl):S34–48.CrossRefPubMedGoogle Scholar
  20. 20.
    Huang M, Lou Y, Pellissier J, Burke T, Liu FX, Xu R, et al. Cost effectiveness of Pembrolizumab vs. standard-of-care chemotherapy as first-line treatment for metastatic NSCLC that expresses high levels of PD-L1 in the United States. PharmacoEconomics. 2017;35(8):831–44. Scholar
  21. 21.
    Oh A, Tran DM, McDowell LC, Keyvani D, Barcelon JA, Merino O, et al. Cost-effectiveness of Nivolumab-Ipilimumab combination therapy compared with monotherapy for first-line treatment of metastatic melanoma in the United States. J Manag Care Spec Pharm. 2017;23(6):653–64. Scholar
  22. 22.
    Temel JS, Greer JA, Muzikansky A, Gallagher ER, Admane S, Jackson VA, et al. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med. 2010;363(8):733–42. Scholar
  23. 23.
    Weber JS, Kahler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30(21):2691–7. Scholar
  24. 24.
    Weber JS. Practical management of immune-related adverse events from immune checkpoint protein antibodies for the oncologist. Am Soc Clin Oncol Educ Book. 2012:174–7.Google Scholar
  25. 25.
    Kourie HR, Awada G, Awada AH. Learning from the “tsunami” of immune checkpoint inhibitors in 2015. Crit Rev Oncol Hematol. 2016;101:213–20. Scholar
  26. 26.
    Gelao L, Criscitiello C, Esposito A, Goldhirsch A, Curigliano G. Immune checkpoint blockade in cancer treatment: a double-edged sword cross-targeting the host as an “innocent bystander”. Toxins (Basel). 2014;6(3):914–33. Scholar
  27. 27.
    Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509–20. Scholar
  28. 28.
    Hodges TR, Ott M, Xiu J, Gatalica Z, Swensen J, Zhou S, et al. Mutational burden, immune checkpoint expression, and mismatch repair in glioma: implications for immune checkpoint immunotherapy. Neuro-Oncology. 2017;19(8):1047–57. Scholar
  29. 29.
    Jin Z, Yoon HH. The promise of PD-1 inhibitors in gastro-esophageal cancers: microsatellite instability vs. PD-L1. J Gastrointest Oncol. 2016;7(5):771–88. Scholar
  30. 30.
    Gainor JF, Shaw AT, Sequist LV, Fu X, Azzoli CG, Piotrowska Z, et al. EGFR mutations and ALK rearrangements are associated with low response rates to PD-1 pathway blockade in non-small cell lung cancer: a retrospective analysis. Clin Cancer Res. 2016;22(18):4585–93. Scholar
  31. 31.
    D’Incecco A, Andreozzi M, Ludovini V, Rossi E, Capodanno A, Landi L, et al. PD-1 and PD-L1 expression in molecularly selected non-small-cell lung cancer patients. Br J Cancer. 2015;112(1):95–102. Scholar
  32. 32.
    Haanen JB, Robert C. Immune checkpoint inhibitors. Prog Tumor Res. 2015;42:55–66. Scholar
  33. 33.
    Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell. 2015;27(4):450–61. Scholar
  34. 34.
    Callahan MK, Wolchok JD. Clinical activity, toxicity, biomarkers, and future development of CTLA-4 checkpoint antagonists. Semin Oncol. 2015;42(4):573–86. Scholar
  35. 35.
    Postow MA, Callahan MK, Wolchok JD. Immune checkpoint blockade in cancer therapy. J Clin Oncol. 2015;33(17):1974–82. Scholar
  36. 36.
    Abdel-Rahman O, Helbling D, Schmidt J, Petrausch U, Giryes A, Mehrabi A, et al. Treatment-related death in cancer patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis. Clin Oncol (R Coll Radiol). 2017;29(4):218–30. Scholar
  37. 37.
    Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–23. Scholar
  38. 38.
    Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013;369(2):134–44. Scholar
  39. 39.
    Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369(2):122–33. Scholar
  40. 40.
    Sznol M, Chen L. Antagonist antibodies to PD-1 and B7-H1 (PD-L1) in the treatment of advanced human cancer. Clin Cancer Res. 2013;19(5):1021–34. Scholar
  41. 41.
    Weber J. Ipilimumab: controversies in its development, utility and autoimmune adverse events. Cancer Immunol Immunother. 2009;58(5):823–30. Scholar
  42. 42.
    Ribas A, Hu-Lieskovan S. What does PD-L1 positive or negative mean? J Exp Med. 2016;213(13):2835–40. Scholar
  43. 43.
    Sul J, Blumenthal GM, Jiang X, He K, Keegan P, Pazdur RFDA. Approval summary: Pembrolizumab for the treatment of patients with metastatic non-small cell lung cancer whose tumors express programmed death-ligand 1. Oncologist. 2016;21(5):643–50. Scholar
  44. 44.
    Jorgensen JT. Companion diagnostic assays for PD-1/PD-L1 checkpoint inhibitors in NSCLC. Expert Rev Mol Diagn. 2016;16(2):131–3. Scholar
  45. 45.
    Ayers M, Lunceford J, Nebozhyn M, Murphy E, Loboda A, Kaufman DR, et al. IFN-gamma-related mRNA profile predicts clinical response to PD-1 blockade. J Clin Invest. 2017;127(8):2930–40. Scholar
  46. 46.
    Nishijima TF, Muss HB, Shachar SS, Moschos SJ. Comparison of efficacy of immune checkpoint inhibitors (ICIs) between younger and older patients: a systematic review and meta-analysis. Cancer Treat Rev. 2016;45:30–7. Scholar
  47. 47.
    Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017;376(11):1015–26. Scholar
  48. 48.
    Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016;375(19):1823–33. Scholar
  49. 49.
    Carbone DP, Reck M, Paz-Ares L, Creelan B, Horn L, Steins M, et al. First-line Nivolumab in stage IV or recurrent non-small-cell lung cancer. N Engl J Med. 2017;376(25):2415–26. Scholar
  50. 50.
    Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373(17):1627–39. Scholar
  51. 51.
    Wang C, Yu X, Wang WA. Meta-analysis of efficacy and safety of antibodies targeting PD-1/PD-L1 in treatment of advanced nonsmall cell lung cancer. Medicine (Baltimore). 2016;95(52):e5539. Scholar
  52. 52.
    Morgensztern D, Herbst RS. Nivolumab and Pembrolizumab for non-small cell lung cancer. Clin Cancer Res. 2016;22(15):3713–7. Scholar
  53. 53.
    Xia B, Herbst RS. Immune checkpoint therapy for non-small-cell lung cancer: an update. Immunotherapy. 2016;8(3):279–98. Scholar
  54. 54.
    Haanen JB, Thienen H, Blank CU. Toxicity patterns with immunomodulating antibodies and their combinations. Semin Oncol. 2015;42(3):423–8. Scholar
  55. 55.
    Friedman CF, Snyder A. Atypical autoimmune adverse effects with checkpoint blockade therapies. Ann Oncol. 2017;28(2):206–7. Scholar
  56. 56.
    •• Cherny NI, Sullivan R, Dafni U, Kerst JM, Sobrero A, Zielinski C, et al. A standardised, generic, validated approach to stratify the magnitude of clinical benefit that can be anticipated from anti-cancer therapies: the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS). Ann Oncol. 2015;26(8):1547–73. This criteria for gauging meaningful responses put together by ESMO is very helpful for clinicians to use when evaluating treatment responses. CrossRefPubMedGoogle Scholar
  57. 57.
    Abdel-Rahman O, Fouad MA. Network meta-analysis of the risk of immune-related renal toxicity in cancer patients treated with immune checkpoint inhibitors. Immunotherapy. 2016;8(5):665–74. Scholar
  58. 58.
    De Velasco G, Je Y, Bosse D, Awad MM, Ott PA, Moreira RB, et al. Comprehensive meta-analysis of key immune-related adverse events from CTLA-4 and PD-1/PD-L1 inhibitors in cancer patients. Cancer Immunol Res. 2017;5(4):312–8. Scholar
  59. 59.
    Costa R, Costa RB, Talamantes SM, Helenoswki I, Carneiro BA, Chae YK, et al. Analyses of selected safety endpoints in phase 1 and late-phase clinical trials of anti-PD-1 and PD-L1 inhibitors: prediction of immune-related toxicities. Oncotarget. 2017;
  60. 60.
    Larkin J, Hodi FS, Wolchok JD. Combined Nivolumab and Ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(13):1270–1. Scholar
  61. 61.
    Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined Nivolumab and Ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(1):23–34. Scholar
  62. 62.
    McNicol ED, Ferguson MC, Schumann R. Methadone for neuropathic pain in adults. Cochrane Database Syst Rev. 2017;5:CD012499.PubMedGoogle Scholar
  63. 63.
    • Chen TW, Razak AR, Bedard PL, Siu LL, Hansen AR. A systematic review of immune-related adverse event reporting in clinical trials of immune checkpoint inhibitors. Ann Oncol. 2015;26(9):1824–9. This is a very good review of adverse event reporting in checkpoint inhibitor trials. It is evident that there are differences in the rigor of reporting on one hand tumor responses and survival and on the other hand adverse effects and quality of life. CrossRefPubMedGoogle Scholar
  64. 64.
    • Ioannidis JP, Evans SJ, Gotzsche PC, O’Neill RT, Altman DG, Schulz K, et al. Better reporting of harms in randomized trials: an extension of the CONSORT statement. Ann Intern Med. 2004;141(10):781–8. It is interesting that the CONSORT statement and guidelines to reporting adverse effects in trials has been in existence for over 10 years yet there are large gaps in reporting still. CrossRefPubMedGoogle Scholar
  65. 65.
    Matter-Walstra K, Schwenkglenks M, Aebi S, Dedes K, Diebold J, Pietrini M, et al. A cost-effectiveness analysis of Nivolumab versus docetaxel for advanced nonsquamous NSCLC including PD-L1 testing. J Thorac Oncol. 2016;11(11):1846–55. Scholar
  66. 66.
    Kohn CG, Zeichner SB, Chen Q, Montero AJ, Goldstein DA, Flowers CR. Cost-effectiveness of immune checkpoint inhibition in BRAF wild-type advanced melanoma. J Clin Oncol. 2017;35(11):1194–202. Scholar
  67. 67.
    Wang J, Chmielowski B, Pellissier J, Xu R, Stevinson K, Liu FX. Cost-effectiveness of Pembrolizumab versus Ipilimumab in Ipilimumab-naive patients with advanced melanoma in the United States. J Manag Care Spec Pharm. 2017;23(2):184–94. Scholar
  68. 68.
    Aguiar PN Jr, Perry L, Penny-Dimr J, Babiker H, Tadokoro H, de Mello RA, et al. The effect of PD-L1 testing on the cost-effectiveness and economic impact of immune checkpoint inhibitors for the second-line treatment of NSCLC. Ann Oncol. 2017;28(9):2256–63. Scholar
  69. 69.
    Huang M, Lou Y, Pellissier J, Burke T, Liu FX, Xu R, et al. Cost-effectiveness of pembrolizumab versus docetaxel for the treatment of previously treated PD-L1 positive advanced NSCLC patients in the United States. J Med Econ. 2017;20(2):140–50. Scholar
  70. 70.
    Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015;372(21):2018–28. Scholar
  71. 71.
    Franklin C, Livingstone E, Roesch A, Schilling B, Schadendorf D. Immunotherapy in melanoma: recent advances and future directions. Eur J Surg Oncol. 2017;43(3):604–11. Scholar
  72. 72.
    • Tempero M. Reducing the cost of cancer care: when less is more. J Natl Compr Canc Netw. 2017;15(7):853. This is a short editorial but the ideas set forth are worth considering. CrossRefPubMedGoogle Scholar
  73. 73.
    Blumenthal GM, Kluetz PG, Schneider J, Goldberg KB, McKee AE, Pazdur R. Oncology drug approvals: evaluating endpoints and evidence in an era of breakthrough therapies. Oncologist. 2017;22(7):762–7. Scholar
  74. 74.
    Chabner BA. Regarding “oncology drug approvals: evaluating endpoints and evidence in an era of breakthrough therapies”. Oncologist. 2017;22(7):757–8. Scholar
  75. 75.
    mcNeil. misunderstandings. Lancet Oncology.Google Scholar
  76. 76.
    McNeil CM, Tattersall MHN. Misunderstandings, mandatory biopsies, and conflicts of interests in clinical trials: a coercive cocktail? Lancet Oncol. 2017;18(7):851–2. Scholar
  77. 77.
    Greer JA, Pirl WF, Jackson VA, Muzikansky A, Lennes IT, Gallagher ER, et al. Perceptions of health status and survival in patients with metastatic lung cancer. J Pain Symptom Manag. 2014;48(4):548–57. Scholar
  78. 78.
    Experts in Chronic Myeloid L. The price of drugs for chronic myeloid leukemia (CML) is a reflection of the unsustainable prices of cancer drugs: from the perspective of a large group of CML experts. Blood. 2013;121(22):4439–42. Scholar
  79. 79.
    Mailankody S, Prasad V. Five years of cancer drug approvals: innovation, efficacy, and costs. JAMA Oncol. 2015;1(4):539–40. Scholar
  80. 80.
    Amir E, Seruga B, Martinez-Lopez J, Kwong R, Pandiella A, Tannock IF, et al. Oncogenic targets, magnitude of benefit, and market pricing of antineoplastic drugs. J Clin Oncol. 2011;29(18):2543–9. Scholar
  81. 81.
    Hoch JS, Sabharwal M. Informing Canada’s cancer drug funding decisions with scientific evidence and patient perspectives: the Pan-Canadian Oncology Drug Review. Curr Oncol. 2013;20(2):121–4. Scholar
  82. 82.
    Homsi J, Walsh D, Rivera N, Rybicki LA, Nelson KA, Legrand SB, et al. Symptom evaluation in palliative medicine: patient report vs systematic assessment. Support Care Cancer. 2006;14(5):444–53. Scholar
  83. 83.
    Basch E. Patient-reported outcomes - harnessing Patients’ voices to improve clinical care. N Engl J Med. 2017;376(2):105–8. Scholar
  84. 84.
    Basch E, Deal AM, Dueck AC, Scher HI, Kris MG, Hudis C, et al. Overall survival results of a trial assessing patient-reported outcomes for symptom monitoring during routine cancer treatment. JAMA. 2017;318(2):197–8. Scholar
  85. 85.
    Basch E, Dueck AC, Rogak LJ, Minasian LM, Kelly WK, O’Mara AM, et al. Feasibility assessment of patient reporting of symptomatic adverse events in multicenter cancer clinical trials. JAMA Oncol. 2017.Google Scholar
  86. 86.
    Kesselheim AS, Woloshin S, Eddings W, Franklin JM, Ross KM, Schwartz LM. Physicians’ knowledge about FDA approval standards and perceptions of the “breakthrough therapy” designation. JAMA. 2016;315(14):1516–8. Scholar
  87. 87.
    Earle CC, Neville BA, Landrum MB, Ayanian JZ, Block SD, Weeks JC. Trends in the aggressiveness of cancer care near the end of life. J Clin Oncol. 2004;22(2):315–21. Scholar
  88. 88.
    Cheung MC, Earle CC, Rangrej J, Ho TH, Liu N, Barbera L, et al. Impact of aggressive management and palliative care on cancer costs in the final month of life. Cancer. 2015;121(18):3307–15. Scholar
  89. 89.
    Peppercorn J. Financial toxicity and societal costs of cancer care: distinct problems require distinct solutions. Oncologist. 2017;22(2):123–5. Scholar
  90. 90.
    Gyawali B, Sullivan R. Economics of cancer medicines: for whose benefit? New Bioeth. 2017;23(1):95–104. Scholar

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Authors and Affiliations

  1. 1.Geisinger Medical SystemDanvilleUSA

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